The present invention is related to catechin multimers and their use as carrier moieties for the delivery of nucleophilic and/or cationic bioactive therapeutic agents to target sites in vivo. For example, substituted catechin multimers of the present invention may be administered alone, for the treatment of stenotic vascular diseases and disorders, such as atherosclerosis (also known as arteriosclerosis) and coronary heart disease (also known as coronary artery disease and ischemic heart disease). Alternatively, catechin multimers, substituted and otherwise, may be complexed with nucleophilic and/or cationic bioactive therapeutic agents, such as anti-thrombotic agents, cholesterol lowering agents, anti-plaque agents, anti-cancer agents, chemotherapeutic agents, anti-inflammatory agents, antibiotics, antimicrobials, wound healing agents, and the like, for the treatment of a variety of diseases and disorders, including but not limited to, vascular and cardiac stenoses, cancer, inflammatory conditions, neurological conditions, infections, burns, wounds, etc. Catechin multimers, particularly the substituted catechin multimers described herein, have a strong affinity for polar proteins residing in the vascular endothelium as well as the walls and membranes of other select cells and tissues, and, accordingly, are able to provide targeted delivery of bioactive agents embedded therein and/or complexed therewith so as to potentiate their therapeutic effects.
Many diseases or disorders are characterized by localized pathology, i.e., affecting only select cells, tissues or organs. Examples of such diseases or disorders include but are not limited to cancers, stenotic vascular disorders such as atherosclerosis (or arteriosclerosis), inflammatory disorders, infections, wounds, burns, and certain neurological conditions. Treatment modalities for such diseases often rely on the ability to target bioactive agents to a diseased region or tissue in the body of a patient, while minimizing or preventing action of the bioactive agents on other regions or tissues in the body, such as undiseased regions or tissues. In other words, in treating such conditions, it is desirable to direct the appropriate drug to the affected area while at the same time avoiding unacceptable or toxic side effects to healthy tissue. Targeted drug delivery means are particularly important where the toxicity of the drug is an issue. Specific tissue targeting drug delivery methods potentially serve to minimize toxic side effects, lower the required dosage amounts, and decrease costs for the patient.
Various methods for targeted delivery of bioactive agents are described in the literature. For example, one method involves the use of liposomes as delivery vehicles. Alternatively, structural features, such as receptor proteins and cell-specific antigens, have also been used in targeting delivery of a bioactive agent to a particular region or tissue. However, such structural features are associated with one or, at most a few, disease states. In addition, incomplete or irregular expression of such structural features may further limit their usefulness in targeted delivery of bioactive agents. Moreover, delivery of effective doses of bioactive agents to target cells is hampered by many factors, including but not limited to, low residence times in serum, ineffective targeting, loss of the therapeutic agent in solution before it may be taken up by the target cell, and degradation of the therapeutic in the endosomic/lysosomic pathway.
Accordingly, there is a need in the art to provide new and/or improved methods for targeting specific cells or tissues in the body of a patient, and delivering bioactive agents to such targeted cells or tissues. The present invention is directed to these, as well as other, important ends.
As demonstrated herein, catechins, including epi and other carbo-cationic isomers and derivatives thereof, can as monomers, dimers and higher multimers can form complexes with nucleophilic and cationic bioactive agents. Catechin multimers have a strong affinity for polar proteins, such as those residing in the vascular endothelium, and on cell/organelle membranes. Thus, as discussed in detail herein, such catechin compounds find particular utility in the targeted delivery of bioactive agents to select sites in vivo.
Accordingly, it is an object of the invention is to provide therapeutic compositions and methods of using same to treat stenotic vascular diseases and disorders, such as atherosclerosis and coronary artery disease, comprising an effective amount of a substituted catechin multimer. In a preferred embodiment, the substituted catechin multimer is an amidated catechin multimer, a complex formed from the reaction between catechin and nitrogen containing moities such as ammonia (NH3).
Nitric oxide (NO) and cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate (cGMP) have been reported to prevent vascular smooth muscle cell proliferation and have beneficial effects to reduce intimal thickening in response to arterial injury (See Boerth N J et al., J Vasc Res July-August 1997;34(4):245-59). Furthermore, endothelial dysfunction associated with atherosclerosis has been attributed to alterations in the L-arginine-nitric oxide (NO)-cGMP pathway or to an excess of endothelin-1 (ET-1) (See Hernandez-Perera O et al., J Clin Invest Jun. 15, 1998;101(12):2711-9). Accordingly, endothelial NO-cGMP signaling appears to be involved in the attenuation of atherosclerosis and inhibition of platelet aggregation. Though not wishing to be bound by theory, it is believed that these substituted catechin multimers, through their affinity for polar proteins of the vascular lining, direct delivery of the nitrogen moieties embedded therein to the vascular endothelium. The nitrogen moieties then stimulate NO-cGMP signaling, which, in turn, attenuates atherosclerosis and platelet aggregation. Thus, in the above context, xe2x80x9ctreatmentxe2x80x9d involves one or more of the following: (a) the reduction of plaque formation of the vascular walls; (b) the reversal of plaque deposition and degenerative changes in the arterial walls; and (c) the removal or stabilization of existing vascular plaques; or (d) the enhancement of cholesterol solubility in plasma.
In one embodiment, the substituted catechin multimers, alone or in combination with other bioactive agents, are particularly effective in encouraging or increasing cholesterol solubility and also in reversing the arterial plaque deposition and degenerative changes to substantially arrest, alleviate and, to a certain extent, even cure the many and varied problems, conditions and secondary complications associated with atherosclerosis.
In another embodiment, the substituted catechin multimers and methods of using same provide for the inhibition of the formation (e.g., progression) of atherosclerotic plaques and/or the removal of existing plaque from vascular walls of animals, particularly humans. The therapeutic compositions and methods may further aid in stabilizing plaques. By xe2x80x9cplaque stabilizationxe2x80x9d, it is meant the inhibition of plaque passing through a phase in which the lipid core has grown and the fibrous cap is very thin and vulnerable to rupture due to an increase in the density of macrophages.
It is another object of the present invention to provide therapeutic compositions and methods of using same for the targeted delivery of bioactive agents to select sites in vivo, comprising an effective amount of a catechin multimer, particularly a substituted catechin multimer, complexed with a nucleophilic and cationic bioactive agent. In order to facilitate formation of the complex, the bioactive agent should be either naturally nucleophilic and/or cationic or modified to be so. The catechin multimer acts as a xe2x80x9ccarrierxe2x80x9d for the bioactive agent, targeting the tissue of interest, such as the vascular endothelium or the mitochondrial membrane and delivering the therapeutic agent embedded therein to the targeted site. The bioactive agent is preferably selected from the group consisting of anti-thrombotics, cholesterol lowering agents, anti-plaque agents, anti-cancer agents, chemotherapeutics, anti-inflammatory agents, antibiotics, antimicrobials, wound healing agents, and the like.
It is further object of the present invention to provide a method for treating diseases or disorders associated with localized pathology. Examples of such diseases and disorders include but are not limited to cardiac and vascular stenoses, cancer, inflammatory conditions, neurological conditions, infection, wounds, burns and the like.
In one embodiment, the therapeutic composition comprises a catechin multimer, particularly a substituted catechin multimer, complexed with a bioactive anti-cancer or chemotherapeutic agent. The catechin multimer facilitates the targeted delivery of the bioactive agent to the inner mitochondrial membrane of the cancer cell and can stimulate the release of mitochondrial cytochrome c necessary for proper apoptosis.
In another embodiment, the therapeutic composition comprises a catechin multimer, particularly a substituted catechin-ligand multimer, complexed with a bioactive anti-inflammatory agent. The catechin multimer facilitates the targeted delivery of the bioactive agent to an inflamed site and inhibits adhesion of platelets and macrophages. Examples of inflammatory conditions that may be amenable to treatment with such therapeutic compositions include but are not limited to autoimmune disorders (e.g., rheumatoid arthritis and systemic lupus erythematosus), myocarditis, nephritis, ulcerative colitis, inflammatory bowel disease (e.g., Crohn""s disease).
In another embodiment, the therapeutic composition comprises a catechin multimer, particularly a substituted catechin multimer, complexed with a bioactive antibiotic or antimicrobial agent, such as zinc or bismuth. The catechin multimer facilitates the targeted delivery of the bioactive agent to an infected site.
The therapeutic compositions of the present invention may be pharmaceutically formulated xe2x80x9cneatxe2x80x9d or with one or more excipient or additives. For example, therapeutic compositions may comprise one or more stabilizing agents, such as salts, tannic acid, ascorbic acid lecithin, and tocopherols. In one preferred embodiment, the stabilizing agent comprises about 10 wt. % to about 60 wt. % of the entire composition.